There is an urgent and unmet need for effective treatment methods for stroke patients who have suffered debilitating loss of nervous tissue and neural function. Development of neuroregeneration therapy is an important goal because neurological disorders such as stroke disable and kill millions of people worldwide each year, yet a viable therapeutic option is not available. Discovery of neural stem cells (NSCs) in the aging brain and in stroke patients has sparked interest in the development of new approaches to boost the body's natural ability to create healthy new cells from endogenous stem cells. Recently, we made the serendipitous discovery that a small molecule heterocyclic pyrimidine derivative can speed up the growth of human neural stem cells grown in culture. Subsequent preliminary analysis in rodents suggested that the molecule can accelerate neurogenesis in animals as well, apparently without any ill effects. Based on these early observations, we are hypothesizing that administration of the compound will stimulate new brain cell formation leading to improved neural function. To test this, we are proposing to conduct a series of quantitative cell culture assays and animal studies to determine whether: (a) the compound can accelerate the growth of human neural stem cell without adversely affecting other cell types or increasing tumor cell growth (b) the newly formed cells are fully capable of differentiating into neurons and other cell types that typically populate the brain, (c) when injected in normal adult mice, the compounds will induce normal neurogenesis in a dose dependent manner, and (d) when injected in a mouse model of stroke, there will be a significant rise in neurogenesis, with potential for improvement of neural function. Immunohistological assays, growth assays, and behavioral tests will be used to quantify the compound's activity. Upon the completion of these experiments, we expect to confirm the feasibility of using the pyrimidine derivative to promote dose dependent neurogenesis in cell and animal models without inducing obviously deleterious effects. In Phase II, we will conduct detailed safety, distribution, and efficacy studies on the molecule, in preparation for carrying out IND- enabling studies during Phase III. This project is innovative because our test compound offers a novel approach for inducing new brain cell growth in patients with neurodegenerative diseases. We are proposing to test a new small molecule drug candidate that can boost the body's natural ability to regenerate brain cells from endogenous neural stem cells. When successful, our drug candidate will offer a new treatment alternative for patients with neurodegenerative diseases such as stroke, Alzheimer's disease, Parkinson's and ALS. [unreadable] [unreadable] [unreadable]